Vitamin B-6-Induced Neuropathy: Exploring the Mechanisms of Pyridoxine Toxicity.

Vitamin B-6 in the form of pyridoxine (PN) is commonly used by the general population. The use of PN-containing supplements has gained lots of attention over the past years as they have been related to the development of peripheral neuropathy. In light of this, the number of reported cases of adverse health effects due to the use of vitamin B-6 have increased. Despite a long history of study, the pathogenic mechanisms associated with PN toxicity remain elusive. Therefore, the present review is focused on investigating the mechanistic link between PN supplementation and sensory peripheral neuropathy. Excessive PN intake induces neuropathy through the preferential injury of sensory neurons. Recent reports on hereditary neuropathy due to pyridoxal kinase (PDXK) mutations may provide some insight into the mechanism, as genetic deficiencies in PDXK lead to the development of axonal sensory neuropathy. High circulating concentrations of PN may lead to a similar condition via the inhibition of PDXK. The mechanism behind PDXK-induced neuropathy is unknown; however, there is reason to believe that it may be related to γ-aminobutyric acid (GABA) neurotransmission. Compounds that inhibit PDXK lead to convulsions and reductions in GABA biosynthesis. The absence of central nervous system-related symptoms in PDXK deficiency could be due to differences in the regulation of PDXK, where PDXK activity is preserved in the brain but not in peripheral tissues. As PN is relatively impermeable to the blood-brain barrier, PDXK inhibition would similarly be confined to the peripheries and, as a result, GABA signaling may be perturbed within peripheral tissues, such as sensory neurons. Perturbed GABA signaling within sensory neurons may lead to excitotoxicity, neurodegeneration, and ultimately, the development of peripheral neuropathy. For several reasons, we conclude that PDXK inhibition and consequently disrupted GABA neurotransmission is the most plausible mechanism of toxicity.

[Peripheral neuropathy with hypervitaminosis B6 caused by self-medication]. / Neuropathie périphérique avec hypervitaminose B6 provoquée par l'automédication.

INTRODUCTION: Vitamin B6 is contained in a number of over-the-counter drugs and vitamin supplements. It may cause severe neurological troubles in case of overdosage. CASE REPORT: We report the case of a 92-year-old women with gait disorders. A diagnosis of peripheral neuropathy with both motor and sensitive deficits was established and investigated. Blood level of vitamin B6 was measured to investigate a potential deficiency. Unexpectedly, the results showed hypervitaminosis B6, which appears to be due to self-administration of an over-the-counter drug containing vitamin B6. Discontinuation of this drug was associated with decrease in vitamin B6 level as well as gait improvement. We also discuss the toxicity of vitamin B6. CONCLUSION: Hypervitaminosis B6 remains a possible cause of peripheral neuropathy and it may be caused by self-administration of over-the-counter vitamin-containing drugs.

High methionine, low folate and low vitamin B6/B12 (HM-LF-LV) diet causes neurodegeneration and subsequent short-term memory loss.

Methionine is an essential amino acid found in rich quantities in average American diet such as meats, fish and eggs. Excessive consumption of such food often exceeds the normal requirement of the methionine in our body; which found to be related to the development of neurodegenerative disorders. However, the mechanistic pathways of methionine's influence on the brain are unclear. The present study is focus on the effects of high methionine, low folate and low vitamin B6/B12 (HM-LF-LV) diet on the dysfunction of neuronal and vascular specific markers in the brain. C57BL6/J male mice (8-10 week old) were fed with HM-LF-LV diet for a 6 week period. Cognitive function of mice was determine by measuring short-term memory using a Novel Object Recognition test (NORT). Neuronal dysfunction were evaluate by measuring the levels of Neuronal nuclear antigen (NeuN), Neuron-specific-enolase (NSE) and Fluoro-jade C(FJC) fluorescence; while cerebrovascular disruption were evaluate by assessing levels of endothelial junction proteins Vascular Endothelial-Cadherin (VE-Cadherin) and Claudin-5 in harvested brain tissue. Cerebrovascular permeability was assess by evaluating microvascular leakage of fluorescently labeled albumin in vivo. Endothelial and Neuronal Nitric Oxide Synthase (eNOS, nNOS) regulation and vascular inflammation (ICAM: intercellular adhesion molecules) were also evaluate in brain tissue. All assessments were conduct at weekly intervals throughout the study duration. NORT showed a significant temporal decrease in short-term memory of mice fed on HM-LF-LV diet for 6 weeks compared to the wild-type control group. Our experimental data showed that neuronal dysfunction (decreased NeuN levels and increased FJC positive neurons in brain) was more prominent in HM-LF-LV diet fed mice compared to normal diet fed control mice. In experimental mice, cerebrovascular disruption was found to be elevated as evident from increased pial venular permeability (microvascular leakage) and decreased in VE-Cadherin expression compared to control. Slight decrease in nNOS and increase in eNOS in experimental mice suggest a trend towards the decrease in potential for neuronal development due to the long-term HM-LF-LV diet fed. Collectively, our results suggest that a diet containing high methionine, low folate and low vitamin B6/B12 results in increased neuronal degeneration and vascular dysfunction, leading to short-term memory loss. Interestingly, significant neuronal damage precedes vascular dysfunction.

A 7-day intravenous toxicity study and neurotoxicity assessment of pyridorin in Sprague-Dawley rats.

Pyridorin®, a naturally occurring metabolite of vitamin B6 that inhibits and scavenges reactive oxygen species, is being developed as a potential therapeutic for acute kidney injury. An investigational new drug application (IND) was opened for Pyridorin in support of its ongoing oral drug clinical development program. Currently, a Pyridorin intravenous (IV) formulation is being developed for use in surgical patients. To support the IND for Pyridorin, a full battery of nonclinical Good Laboratory Practice compliant studies was performed with no neurological or behavioral signs of toxicity seen following oral or IV administration of pyridoxine dihydrochloride (the active ingredient in Pyridorin). However, excessive ingestion of vitamin B6 has been reported to cause neurotoxic syndrome in humans. Therefore, under Food and Drug Administration recommendation, a 7-day IV study in rats was conducted to further evaluate the drug's potential to cause neurotoxicity. Blood plasma samples indicated that exposure to pyridoxamine dihydrochloride and its metabolites, pyridoxal, pyridoxine, and 4-pyridoxic acid was linearly dose proportional and independent of gender. At doses of up to 200 mg/kg/day pyridoxine dihydrochloride, no treatment-related effects were seen in rats, providing further evidence for the absence of pyridoxine dihydrochloride-related changes in the nervous system. A no observed adverse effect level of 200 mg/kg/day was identified for this study.

VITAMIN B6 (PYRIDOXINE HYDROCHLORIDE) TOXICOSIS IN FALCONS.

This manuscript reports three independent accidental cases of vitamin (Vit) B6 toxicosis in gyrfalcons (Falco rusticolus) and peregrine falcons (Falco peregrinus) and a toxicology study that was conducted to characterize the clinical responses of gyrfalcons and gyrfalcon × peregrine falcons to a range of single intramuscular (IM) and oral (PO) doses of Vit B6. Both lethal and nonlethal doses were determined. Twelve female gyrfalcons died following IM injection of 1 ml of a vitamin B preparation. Within 30 min of injection, the birds passed pistachio green-colored urates and progressed to vomiting, anorexia, cessation of normal activity, ptosis, collapse, and death, occurring 24-36 hr post injections. Three individuals vomited frothy, partially digested blood and had clonic spasms and convulsions. Postmortem and histopathology revealed multifocal severe hepatic necrosis, splenic lymphoid tissue depletion and hemorrhages with arterial necrosis, and acute renal tubular necrosis. Following administration of a different, oral, mineral-vitamin supplement, a total of 21 peregrine falcons in two separate European facilities died suddenly. Histology of the liver showed diffuse congestion and multifocal coagulative necrosis with mild infiltration of heterophils. The particular nutritional supplement, used by both breeders, was analyzed and found to contain 5-9.7% Vit B6. Other randomly selected lots of the product contained 0.007-0.27% Vit B6. According to the product label, Vit B6 should have been present at 0.004%. To confirm the hypothesis that Vit B6 was responsible for the deaths of the falcons in Abu Dhabi, Vit B6 (British Pharmacopoeia [BP] grade) in powder form was diluted in water for injection and administered IM to four groups of falcons. Groups of four gyrfalcon × peregrine hybrid falcons or gyrfalcons (or both) were given a single IM dose of 5, 10, 15, or 20 mg/kg of Vit B6 or received an oral dose of 25, 50, or 75 mg of Vit B6. Only birds in the lowest-dose groups survived. The maximum nonlethal single doses of Vit B6 in falcons were 5 mg/kg i.m. and 25 mg/kg p.o.

Effects of maternal vitamin B6 deficiency and over-supplementation on DNA damage and oxidative stress in rat dams and their offspring.

Vitamin B6 is a cofactor for more than 140 essential enzymes and plays an important role in maternal health and fetal development. The goal of this study was to investigate the effects of maternal vitamin B6 on DNA damage and oxidative stress status in rat dams and their offspring. Female Wistar rats were randomly assigned to three dietary groups fed a standard diet (control diet), a diet supplemented with 30 mg/kg of vitamin B6, or a deficient diet (0 mg/kg of vitamin B6) for 10 weeks before and during mating, pregnancy and lactation. The dams were euthanized at weaning, and their male pups were euthanized either 10 days or 100 days after birth. We found that maternal vitamin B6 deficiency increased the micronucleus frequency in peripheral blood and bone marrow cells and also increased the concentration of hepatic TBARS (thiobarbituric acid reactive substances) in newborn pups (10 days old). In conclusion, maternal 5- to 6-fold over-supplementation of vitamin B6 had no adverse effects, however its deficiency may induce chromosomal damage and hepatic lipid peroxidation in the offspring.

Micronutrients and women of reproductive potential: required dietary intake and consequences of dietary deficiency or excess. Part I--Folate, Vitamin B12, Vitamin B6.

This two-part review highlights micronutrients for which either public health policy has been established or for which new evidence provides guidance as to recommended intakes during pregnancy. One pivotal micronutrient is folate, the generic name for different forms of a water-soluble vitamin essential for the synthesis of thymidylate and purines and, hence, DNA. For non-pregnant adult women the recommended intake is 400 µg/day dietary folate equivalent. For women capable of becoming pregnant an additional 400 µg/day of synthetic folic acid from supplements or fortified foods is recommended to reduce the risk of neural tube defects (NTD). The average amount of folic acid received through food fortification (grains) in the US is only 128 µg/day, emphasising the need for the supplemental vitamin for women of reproductive age. Vitamin B12 (cobalamin) is a cofactor required for enzyme reactions, including generation of methionine and tetrahydrofolate. B12 is found almost exclusively in foods of animal origin (meats, dairy products); therefore, vegetarians are at greatest risk for dietary vitamin B12 deficiency and should be supplemented. Vitamin B6 is required for many reactions, primarily in amino acid metabolism. Meat, fish and poultry are good dietary sources. Supplementation beyond routine prenatal vitamins is not recommended.

Evaluation of the clastogenicity and anticlastogenicity of vitamin B6 in human lymphocyte cultures.

Insufficient intakes of many micronutrients found in fruits and vegetables, such as folic acid, vitamins C and B6 may lead to DNA damage, cancer, and degenerative disease. The investigation of dietary antioxidants is a field of great interest for elucidating mechanisms of mutagenesis/carcinogenesis. The present study was undertaken to investigate the effects of vitamin B6 on the induction of chromosomal aberrations in cultured human lymphocytes and to examine the possible anticlastogenic effect of this vitamin on chromosomal damage induced by the antitumor drug doxorubicin. The results showed that when the cultures treated with vitamin B6 were compared with the untreated control in terms of total chromosomal damage and abnormal metaphases, pre- and simultaneous treatment with this vitamin showed no significant differences. In the post-treatment, average and above average concentrations of vitamin B6 alone showed a clastogenic effect. In the simultaneous protocol, this vitamin (15, 90 and 120 microg/mL) was effective in inhibiting chromosomal aberrations induced by doxorubicin (p<0.05), with a reduction of 33.1% with the highest concentration tested. However, in the post-treatment, the associations of vitamin B6 and doxorubicin exerted a more evident clastogenic effect than that observed in the cultures exposed only to the antitumor drug. In the present investigation, the inability of vitamin B6 to decrease chromosomal damage induced by doxorubicin in the pre- and post-treatments could be justified by the instability of this vitamin as a free radical scavenger. In conclusion, the results from this study confirmed that vitamin B6 is protective against chromosomal damage induced by doxorubicin in cultured human lymphocytes, but that the effects depend on concentration and form of treatment.

Effects of excess vitamin B6 intake on cerebral cortex neurons in rat: an ultrastructural study.

The aim of this study was to investigate whether excess of vitamin B6 leads to ultrastructural changes in cerebral cortex of forty-eight healthy albino rats which were included in the study. Saline solution was injected to to the control groups (CG-10, n = 12 for 10 days; CG-15, n = 12 for 15 days; CG-20, n=12 for 20 days). The three experimental groups (EG-10, n = 12; EG-15, n = 12; EG-20, n = 12) were treated with 5 mg/kg vitamin B6 daily for 10 days (EG-10), 15 days (EG-15) and 20 days (EG-20). Brain tissues were prepared by glutaraldehyde-osmium tetroxide double fixation for ultrastructural analysis. No significant changes were observed in the control groups. The ultrastructural analysis revealed that the numbers of damaged mitochondria, lipofuscin granules and vacuoles were significantly higher in all the experimental groups than in the control groups (p < 0.05). However, synaptic density was significantly decreased in the experimental groups as compared to the control groups (p < 0.05). The results suggest that the excess of vitamin B6 intake causes damage to the cerebral cortex due to cellular intoxication and decreased synaptic density. Thus, careful attention should be paid to the time and dose of vitamin B6 recommended for patients who are supplemented with this vitamin.

[Vitamin B6 (Pyridoxine)--excessive dosage in food supplements and OTC medications].

Vitamin B6 (Pyridoxine) is sold in Israel as a supplement and is available over-the-counter (OTC) without regulation. High intake of this vitamin is found in patients with premenstrual syndrome, carpal tunnel syndrome, pregnancy associated nausea and vomiting, decreasing homocysteine levels and improving cognitive function. Mega-doses of this vitamin may result in intoxication. In this review we will outline vitamin B6 function, daily recommended intake, deficiency signs and patients in deficiency risk, and the clinical spectrum of vitamin B6 intoxication.